Easy Interventions to Improve Male Infertility

Edmund S. Sabanegh, MD

Professor and Chairman, Department of Urology, Cleveland Clinic Lerner College of Medicine; Cleveland, Ohio

Objectives:

• Describe ASRM guidelines for varicocele ligations • Summarize available literature for role of genitourinary infection

in subfertility • Review advances in sperm testing and function essays • Define the role and treatment of oxidative stress in male infertility

Easy Interventions for Male Fertility

Edmund Sabanegh, Jr., M.D.

Chairman, Department of UrologyGlickman Urological and Kidney Institute

Cleveland Clinic

Male SubfertilityMale Subfertility

Etiology Incidence (%)

Varicocele 42

Idiopathic 23

Obstruction 14

Cryptorchidism 3

Immunologic 3

Ejaculatory Dysfunction 1.5

Testicular failure 1.5

Endocrinopathies 1

Other 11

Nagler HM, Martinis FG. Varicocele. In Lipshultz LI, Howards S, editors. Infertility in the Male; 1997

obvious

Male SubfertilityMale Subfertility

Etiology Incidence (%)

Varicocele 42

Idiopathic 23

Obstruction 14

Cryptorchidism 3

Immunologic 3

Ejaculatory Dysfunction 1.5

Testicular failure 1.5

Endocrinopathies 1

Other 11

Nagler HM, Martinis FG. Varicocele. In Lipshultz LI, Howards S, editors. Infertility in the Male; 1997

Not so obviousUltimately, almost 40% of male infertility patients may be candidates for some form of medical therapy

Categories of TherapyCategories of Therapy

Lifestyle Intervention

Specific Medical Therapy

• Endocrinopathy

• Genitourinary Infections

• Ejaculatory Dysfunction

Non-specific (empiric)

• Endocrine

• Antioxidant/ nutraceutical

Personal Health Factors

• Diet

• Exercise

• Obesity

• Stress Oxidative Stress

Endocrine disruptors

Genetic

Tobacco

Smokers were significantly associated with:- lower hypo-osmotic swelling test- lower seminal zinc levels- higher sperm DNA fragmentation percent- higher seminal reactive oxygen species levels

Urology. 2012 Oct;80(4):822-5

Sperm incubated with THC at concentrations equivalent to therapeuticand recreational plasma levels

Marijuana

Fertil Steril. 2006 Mar;85(3):653-60.

31 healthy male volunteers without infertility divided into 2 groups:

Physically Active (n = 16): had practiced endurance activities, except bicycling, for over a

year

Sedentary (n=15): had NOT had regular physical activity during the previous year

Exercise and Fertility

Active men demonstrated higher:- progressive motility

- normal morphology

- serum FSH, LH, and testosterone

- T / Cortisol ratio (indicative of an anabolic state)

Exercise and Fertility

Men (n=188) aged 18–22yrs from the Rochester Young Men’s Study assessed via questionnaire for:

- Physical Activity (hours/week of moderate-vigorous exercise)

- TV watching (hours/week of TV, video, or DVD watching)

Sedentary Lifestyle and Fertility

Br J Sports Med. 2013 Feb 4.

Findings

Sperm concentration and total sperm count - directly related to physical activity after multivariable adjustment.

Men in highest quartile of activity (≥15 hr/wk)- 73% higher sperm concentration than lowest quartile (<5 hr/wk)

TV watching inversely associated with sperm concentration and total count

Sedentary Lifestyle and Fertility

While studies of the association between BMI and semen parameters have yielded conflicting results, there does appear to be a negative relationship between obesity and fertility outcomes as well as endocrine profiles

Review of the Danish National Birth Cohort reveals that among men with a BMI >= 18.5 kg/m2, there exists a dose-response relationship between increasing BMI and subfecundity (time to pregnancy > 12mo). Odds ratio 1.2.

Obesity and Fertility

Fertil Steril. 2011 Apr;95(5):1700-4Retrospective analysis (n=305) of ICSI outcomes demonstrated that increased paternal BMI is associated with:

- decreased blastocyst development

- decreased clinical pregnancy rates

- decreased live birth outcomes

Obesity and Assisted Reproduction

Anabolic SteroidsAnabolic Steroids

Definition: family of hormones which includes testosterone with anabolic (muscle-building) and androgenic (masculinizing) properties

Prevalence- 3 million users in US (Souza, 2011)

Pathophysiology- suppresses hypothalamic-pituitary axis

-low FSH, LH levels

-supraphysiologic serum testo level reduces intratesticular testosterone levels required for spermatogenesis

-severe oligospermia/azoospermia

Anabolic SteroidsAnabolic Steroids

Cessation of steroids- spontaneous recovery in 4-12 months in most although may take up to 5 years (Turek, 1995)

Variety of successful treatment regimens have been reported with small series- hCG alone, hCG/hMG, clomiphene citrate

Practice Patterns of AUA Urologists (N=387)Empiric Medical Therapy for Infertility

Practice Patterns of AUA Urologists (N=387)Empiric Medical Therapy for Infertility

Sabanegh, Brannigan: J Urol, 2012

Endocrinopathy and Male Infertility*Endocrinopathy and Male Infertility*

Excess Insufficiency

Pituitary Hyperprolactinemia Hypogonadotropic Hypogonadism- Kallman’s Syndrome- Acquired insufficiency

Thyroid Hyperthyroidism Hypothyroidism

Androgens Congenital Adrenal HyperplasiaExogenous Steroids

*Account for 3-10% of causes of infertility

HyperprolactinemiaHyperprolactinemia

– Mechanism- complex effects: inhibits GnRH release

– Cause- pituitary adenomas, medications

– Therapy

- remove causes (meds)

- treat macroadenoma (> 1cm dimension,

Prolactin level > 200microgm/L)

» Dopamine agonist therapy (cabergoline 0.125-1.0 mg twice weekly)

» Surgical removal

- Medication therapy for idiopathic

» Cabergoline X 6 months- significant improvements in semen parameters (De Rosa, 2006)

» Fertility in 53% of men on cabergoline (Melmed, 2011)

Hypogonadotropic HypogonadismHypogonadotropic Hypogonadism

Low FSH, LH, testosterone levels

Causes

– Congenital- inadequate GnRH secretion

- Anosmic form or Kallmann’s syndrome

- Idiopathic hypogonadotropic hypogonadism

– Acquired- inadequate GnRH or gonadotropin secretion

Hypogonadotropic HypogonadismHypogonadotropic HypogonadismTherapy

– Gonadotropin Replacement

- LH activity- hCG 1500-2500 IU 3X/week X 3-6 months

- FSH activity- hMG 75-150 IU 3X/week (alternative: recombinant FSH 100-150 IU 2-3X/week)

- 90% of patients will have return of spermatogenesis (Haidl, 2002)

– Pulsatile GnRH (men with intact pituitary function)

– Clomid therapy- effective for select patients presenting post-puberty

Results

– Most conceive with therapy although 71% oligospermic

– Postpubertal onset patients- often respond to hCG alone

– 10% maintain spermatogenesis post treatment cessation (Raivio, 2007)

LeukocytospermiaLeukocytospermia

Agarwal et al, Fert Steril 2008

Associated with

•Lower motility

•Higher seminal oxidative stress

•Antioxidant capacity (TAC)

Genitourinary InfectionGenitourinary InfectionScreen men with leukocytospermia (WHO defn > 1 mil/ml)

elevated oxidative stress (ROS)

Both bacterial and viral (HSV) infections – sperm oxidative damage (Potts, J 2000; Kapranos, 2003)

Antibiotic therapy may improve semen parameters (Vicari, 2000; Sabanegh, 2012)

Reduced oxidative stress

Improved motility and natural conception rates (28 vs. 5%) with therapy of cx+ ureaplasma/chlamydial infection

Addition of NSAID, L-carnitine - incremental benefit over antibiotic alone (Vicari, 2002; Gambera, 2007)

Ejaculatory DysfunctionEjaculatory Dysfunction

Premature ejaculation

Anejaculation

– Spinal cord injury

– Diabetes

– Medications

– Retroperitoneal surgery (RPLND)

– Idiopathic

Retrograde ejaculation

– Bladder neck surgery

– Diabetes

– Medications

Retrograde/ AnejaculationRetrograde/ Anejaculation

– Correct reversible causes (medications)

- Selective serotonin reuptake inhibitors (SSRI) anejaculation

- Alpha blockers retrograde ejaculation

Agent Incidence of reduced ejaculatory volume (%)

Placebo 12

Tamsulosin (0.8mg) 90 (35% anejaculatory)

Alfuzosin 21

Hellstrom, 2006

Retrograde EjaculationRetrograde Ejaculation– Medication regimens (sympathomimetic, anticholinergic)

– Assisted reproduction

- Urinary alkalinization

- Sperm recovery from bladder

- Intrauterine insemination

Medication DosePseudoephedrine 120mg po bidEphedrine sulfate 25mg po bid

Imipramine 25 mg po tid

Why Empiric Therapy?Why Empiric Therapy?Distribution of Final Diagnostic Categories Found in the Male Fertility Clinic

Male factor problem

Idiopathic abnormal semen (OAT syndrome) orno demonstrable causeVaricoceleInfectious factorsImmunological factorsOther acquired factorsCongenital factorsSexual factorsEndocrinal disturbances

Percentage

75.1

12.36.63.12.62.11.70.6

WHO Manual for Standardized Investigation and Diagnosis of the Infertile Couple. Cambridge University Press, 2000

Minimal level 1 evidence

-small uncontrolled series

-poor quantification of interventions

-multiple unidentified confounding variables

Disclosure

Minimal level 1 evidence

-small uncontrolled series

-poor quantification of interventions

-multiple unidentified confounding variables

but, it is what it is…..

Disclosure

Empiric TherapyEmpiric Therapy

Anti-estrogens

Aromatase inhibitors

Gonadotropin-releasing hormone agonists

Gonadotropins

Caveat: these are not FDA approved indications for these medications

Anti-estrogensAnti-estrogens

Mechanism of action

» block estrogen receptors at hypothalamus and pituitary, preventing negative feedback of estrogen on gonadotropin secretion

» Increased GnRH, FSH, LH and resultant increase in serum testosterone (and ? spermatogenesis)

Agents

» Clomiphene citrate

» Tamoxifen citrate

Clomiphene CitrateClomiphene CitrateDose: 12.5-25mg po q day

Side effects: weight gain, hot flashes, mood swings, gynecomastia, decrease in semen count, DVT/PE

Supporting evidence

– Meta-analysis- improved pregnancy rates -odds ratio of 2.47 (O’Donovan, 1993)

– Randomized trial- 58 vs 16% pregnancy rate with clomid vs. control in patients with normal baseline semen parameters (Check, 1989)

– Improved semen parameters but no improvement in pregnancy rates (Wang, 1983; Ronnberg, 1980; Micic, 1985)

Not supporting

– Meta-analysis- no improvement in pregnancy rates (Liu, 2003)

Aromatase InhibitorsAromatase Inhibitors

Mechanism of action

» Aromatase localizes to adipose tissue, liver, testis (Leydig and Sertoli cells)

» Alterations in testosterone/estrogen ratio negatively impacts spermatogenesis

– Decreased LH, FSH levels due to direct feedback inhibition of HPG axis

– Inhibits androgen synthesis in testis

– Direct adverse effect on germ cells

Testosterone Estradiol

Aromatase InhibitorsAromatase Inhibitors

Agents

– Steroidal

Testolactone (50-100mg po bid)

– Non-steroidal

Anastrozole (1mg po daily)

Letrozole

Use- empiric therapy for idiopathic oligospermia in patients with Testosterone/Estrogen ratios of <10

Aromatase InhibitorsTreatment Results

Aromatase InhibitorsTreatment Results

Testolactone (Pavlovich, 2001; Raman, 2002)

- 50-100 mg po bid for 5 months

- Significant increase in T/E2 ratio; Improved semen parameters

Anastrazole (Raman, 2002)

- 1mg po daily for 4-5 months

- Increase T/E2 ratio (5.3 pre treatment to 12.4)

- Semen parameters- count increased from 5.5 mil/cc to 12.4 mil/cc; motility increased from 14 to 21%; morphology improved from 6.5 to 12.8%

- Pregnancy rates were not evaluated

Antioxidant TherapyAntioxidant Therapy

Types– Preventative: metal chelators and metal binding proteins– Scavenger: vitamins E and C, lycopene, carnitine, etc.

Fertility outcomes– Vit E+C supplementation- decreased semen ROS (DeFoor , 2004)– Vit C (200-1000mg/day)- increased sperm counts in infertile males (Dawson,

1987)– Randomized crossover study of Vit E (600IU q day)-improved zona binding but

other parameters unchanged– Cocharane Collaboration meta-analysis (2011- 17 trials)

- Marked heterogeneity in regimens- 82% improvement in sperm quality and/or pregnancy rates

– Improved ICSI outcomes (Greco, 2005)

L-CarnitineL-Carnitine

Effects- mitochondrial metabolism/spermatozoal energy production and motility in epididymis

Infertility and carnitine

– Reduced free and total seminal carnitine levels in infertile men (Zopfgen, 2000)

– Reduced acetyl L-carnitine to L carnitine ratios in patients with reduced motility (Bartellini, 1987)

Antioxidant Therapy with L-CarnitineAntioxidant Therapy with L-Carnitine

Efficacy

– Increased sperm density (Vitali, 1995)

– Improved motility- randomized double blind placebo controlled crossover study- 2 grams/day (Lenzi, 2003)

Empiric Therapy for Male SubfertilityEmpiric Therapy for Male Subfertility

Surveys suggest widespread non-standardized use throughout urologic community

Not FDA approved indication at present

Efficacy conclusions limited by lack of well designed large studies although certainly some small series support anti-estrogen, aromatase inhibitor use in targeted subgroups

Antioxidant therapy has low toxicity profile and potential benefits for idiopathic subfertility patients

Easy Interventions for Male Fertility

Edmund Sabanegh, Jr., M.D.

Chairman, Department of UrologyGlickman Urological and Kidney Institute

Cleveland Clinic

Androgen TherapyAndrogen Therapy

Earliest empiric therapies

» Low dose- “improve epididymal maturation and boost spermatogenesis”

» Rebound- induce azoospermia with improved spermatogenesis in recovery phase

The problem- exogenous testosterone suppresses HPG axis and ultimately lowers intratesticular testosterone levels

Results: meta-analyses -no improvement in fertility (Kamischke, Human Repro, 1999; Liu, Human Repro Update, 2003)

Bottom line- there is no role for routine testosterone therapy in the management of male infertility- in fact, the therapy is counterproductive in most patients

Other Anti-estrogensOther Anti-estrogens

Similar results in tamoxifen trials as clomid

Metanalysis of 10 studies/783 men receiving either clomid or tamoxifen- no difference in pregnancy rates with antiestrogen therapy (Vandekerckhove P, Cochrane Database Sys Rev 2000)

? Role of combination therapy for idiopathic oligospermia

– Randomized study (212 men) between combination of testosterone undecanoate 120mg/d and tamoxifen 20mg/d and placebo (Adamopoulos, 2003)

– Results: significant improvement in semen parameters and pregnancy rate (RR 3.20)

– Study remains to be validated in other trials

Bottom line- there may be a subpopulation of oligospermic patients without other correctable problems that will benefit from empiric anti-estrogen therapy but further properly designed and powered studies are needed to stratify this population

Practice Patterns of AUA Urologists (N=387)Empiric Medical Therapy for Infertility

Practice Patterns of AUA Urologists (N=387)Empiric Medical Therapy for Infertility

Frequent use for idiopathic infertility

– 62% general urologists

– 73% subspecialty trained in male infertility

Indications

Sperm Concentration (mil/ml) Threshold for Use (%)<5 12

5-10 2910-20 32>20 7

Sabanegh, Brannigan: J Urol 2012